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Muscle cell depolarization induces a gain in surface GLUT4 via reduced endocytosis independently of AMPK

¹Programme in Cell Biology, The Hospital for Sick Children; and ²Department of Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 22 November 2005 ; accepted in final form 13 January 2006

Contracting skeletal muscle increases glucose uptake to sustain energy demand. This is achieved through a gain in GLUT4 at the membrane, but the traffic mechanisms and regulatory signals involved are unknown. Muscle contraction is elicited by membrane depolarization followed by a rise in cytosolic Ca²⁺ and actomyosin activation, drawing on ATP stores. It is unknown whether one or more of these events triggers the rise in surface GLUT4. Here, we investigate the effect of membrane depolarization on GLUT4 cycling using GLUT4myc-expressing L6 myotubes devoid of sarcomeres and thus unable to contract. K⁺-induced membrane depolarization elevated surface GLUT4myc, and this effect was additive to that of insulin, was not prevented by inhibiting phosphatidylinositol 3-kinase (PI3K) or actin polymerization, and did not involve Akt activation. Instead, depolarization elevated cytosolic Ca²⁺, and the surface GLUT4myc elevation was prevented by dantrolene (an inhibitor of Ca²⁺ release from sarcoplasmic reticulum) and by extracellular Ca²⁺ chelation. Ca²⁺-calmodulin-dependent protein kinase-II (CaMKII) was not phosphorylated after 10 min of K⁺ depolarization, and the CaMK inhibitor KN62 did not prevent the gain in surface GLUT4myc. Interestingly, although 5'-AMP-activated protein kinase (AMPK) was phosphorylated upon depolarization, lowering AMPK via siRNA did not alter the surface GLUT4myc gain. Conversely, the latter response was abolished by the PKC inhibitors bisindolylmaleimide I and calphostin C. Unlike insulin, K⁺ depolarization caused only a small increase in GLUT4myc exocytosis and a major reduction in its endocytosis. We propose that K⁺ depolarization reduces GLUT4 internalization through signals and mechanisms distinct from those engaged by insulin. Such a pathway(s) is largely independent of PI3K, Akt, AMPK, and CaMKII but may involve PKC.

glucose uptake; glucose transporter-4; calcium; adenosine 5'-monophosphate-activated protein kinase; potassium-induced depolarization

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